Project Summary Diabetic kidney disease (DKD) is the leading cause of renal failure in the United States. Current treatments, such as control of hyperglycemia and hypertension, are beneficial, but only partially protective in patients with type 2 diabetes (T2D). Clinical trials in DKD have yielded disappointing results, partly due to limited understanding of what initiates DKD, a potentially misguided focus on albuminuria, and lack of intervention at an early stage of disease when benefit is most likely. Therefore, identifying new therapeutic targets to impede progression of DKD remains a public health priority. Early DKD, including hyperfiltration, is common in youth with T2D. Renal hypoxia, stemming from a mismatch between renal oxygen utilization and consumption, is increasingly proposed to be a unifying pathway in the development of DKD. The kidneys have a high-energy requirement to sustain normal hemodynamic function. However, in T2D, there are emerging animal data that the kidneys are not able to sufficiently compensate for hyperfiltration and the effects of insulin resistance (IR) on fuel utilization. The pathophysiology underlying the relationship between IR and early DKD in youth-onset T2D is unclear, and it remains unproven whether the relationship is attributed to changes in intrarenal hemodynamic function and/or renal hypoxia. Dedicated translational studies are needed to unravel the complex metabolic pathophysiology behind the development of DKD in T2D. Dr. Bjornstad is establishing himself as a young investigator who is committed to patient-oriented research focused on early DKD. This K23 award would provide Dr. Bjornstad with the support necessary to accomplish the following goals: 1) to define intrarenal hemodynamic function (by iohexol and para-aminohippurate clearance); 2) renal oxygenation and perfusion (by MRI) in T2D youth vs. obese and lean controls, and between T2D youth with and without hyperfiltration; 3) to test the associations between insulin sensitivity (by hyperinsulinemic-euglycemic clamp) with intrarenal hemodynamic function and renal oxygenation. This proposal will provide dedicated time for Dr. Bjornstad to 1) perform translational research in a multi- disciplinary setting that integrates expertise from the fields of endocrinology, nephrology, cardiology and radiology; 2) gain hands-on experience in patient-oriented research, including primary data collection and analysis, study design, and execution; 3) acquire expertise in advanced and unique translational research methods; 4) set the platform for a career as an independent clinical investigator focused on interventional studies that will test novel therapies to impede the development of early DKD. To achieve these goals, Dr. Bjornstad has assembled a nationally-recognized mentoring team led by his primary mentors, Dr. Nadeau, Associate Professor of Pediatric Endocrinology and Dr. Johnson, Chief of Division of Nephrology at University of Colorado, Denver (UCD), in addition a broader mentor team composed of Drs. Truong (Cardiology/Radiology, UCD), Prasad (Radiology, U. of Chicago) and Cherney (Nephrology, U. of Toronto).